Cyclosporins, a group of nonpolar cyclic oligopeptides with immunosuppressant activity, are known to be very poorly soluble in water and are thus difficult to formulate into injectable preparations containing an acceptable quantity of the drug. Due to their poor solubility, cyclosporins have been formulated in various non-aqueous materials including organic solvents such as ethanol and polyoxyethylated castor oils [cremophors] which are potentially toxic.
The patent literature describes various formulations and pharmaceutical presentations of lipophilic drugs. U.S. Pat. No. 4,073,943 to Wretlind describes a carrier system for use in enhancing parenteral administration of a pharmacologically active oil-soluble agent, the carrier system being a stable, oil-in-water emulsion containing a pharmacologically inert lipoid as a hydrophobic phase dispersed in a hydrophilic buffer. The lipoid is dispersed in the emulsion as finely divided particles having a mean diameter of less than 1 micron. The active agent is oil-soluble and is predominantly dissolved in the lipoid. The compositions contain a lipophilic core of a fat of vegetable origin.
In the carrier system described the drug must be soluble in the lipoid, although it may have some solubility in the hydrophilic phase. The composition will usually consist of an inert oil or fat dispersed in an aqueous solution. To obtain a stable emulsion, it is necessary to include a stabilizer of natural or synthetic origin, for example phosphatides, polypropylene glycol, polyethylene glycol or polyglycerol monooleate.
U.S. Pat. No. 4,298,594 to Sears describes the controlled release of an active agent contained in a vehicle in the form of microreservoirs in non-vesicular form having diameters between 250 .ANG. and 1000 .ANG., or vesicular form having diameters ranging between about 190 .ANG. and about 300 .ANG., or both nonvesicular and vesicular forms. The vehicle is formed of a phospholipid constituent and a phospholipid-immiscible lipid constituent. Preferred phospholipid-immiscible lipids include triglyceride and/or cholesterol ester; the phospholipid-immiscible lipid must essentially be immiscible in the phospholipid bilayer. The nonvesicular form is a fat emulsion and the vesicular form is a liposome.
Cyclosporin-containing pharmaceutical formulations for intravenous administration are described in EPO 0 570829 A1 to Dietl. The emulsions are composed of cyclosporin microcrystals in an oily carrier composed of medium-chain triglyceride oil, together optionally with vegetable oil, phospholipid, non-ionic surfactant and ionic surfactant. The lipophilic core composition is composed of natural oil, optionally with free or sodium or potassium salt of a fatty acid.
In the present invention, the lipophilic core composition includes synthetic or derivatized triglycerides and optionally free fatty acids or salts thereof, which are capable of solubilizing more cyclosporin than natural oils and allow the preparation of emulsions with greater cyclosporin payloads. In the present invention, the cyclosporin is completely dissolved in the lipophilic core.
U.S. Pat. No. 4,725,442 to Haynes describes microdroplets from about 100 Angstroms to one micron in diameter having a sphere of a substantially water-insoluble drug dissolved in an organic liquid such as an alkane, a dialkyl ester, a long-chain ester, a hydrophobic ester, a biocompatible silicone, a biocompatible high molecular weight fluorocarbon, oil-soluble vitamin, the liquid and drug surrounded in a layer ofphospholipid.
U.S. Pat. No. 5,342,625 to Hauer describes cyclosporin-containing pharmaceutical compositions in the form of a microemulsion preconcentrate having a hydrophilic phase component of a pharmaceutically acceptable di-or partial-ether or 1,2-propylene glycol; a lipophilic phase component, for instance an organic solvent such as ethanol, and a surfactant; when diluted 1:1 with water an oil-in-water microemulsion having average particle size of less than about 1,000.ANG. is formed. Theses microemulsions do not contain a triglyceride core and are distinctly different from emulsions since they form spontaneously (do not require addition of energy).
U.S. Pat. No. 4,990,337 to Kurihara et al describes emulsions containing cyclosporin and a mixture of medium chain mono- or di-glycerides. The use of medium chain triglycerides and mono- and di-glycerides to solubilize cyclosporin A is discussed. Kurihara concludes that the use of triglycerides, even medium chain triglycerides, is not acceptable due to poor solubility of cyclosporine. The patentees report that cyclosporins have excellent solubility in the mono- and di-glycerides of intermediate molecular weight fatty acids, which are easily emulsified in water, and which can thus substantially improve the dispersibility of cyclosporin in water and aqueous media. However, it is generally known that mono- and di-glycerides have detergent properties which enhance irritation and damage to tissues.
It is an object of this invention to provide a pharmaceutically acceptable cyclosporin preparation with a high drug payload.
It is a further object of this invention to provide a pharmaceutically acceptable cyclosporin preparation without potentially toxic organic solvents such as ethanol and cremophors.
It is another object of this invention to provide a pharmaceutically acceptable cyclosporin preparation which can be used parenterally.
It is an additional object of this invention to provide a pharmaceutically acceptable cyclosporin preparation which can be heat sterilized.
It is a further object of this invention to provide a method of forming such a preparation.